The disclosure of each literature article and published patent document referred to herein is incorporated by reference herein in its entirety.
Cellular transformation during the development of cancer involves multiple alterations in the normal pattern of cell growth regulation. Primary events in the process of carcinogenesis involve the activation of oncogene function by some means (e.g., amplification, mutation, chromosomal rearrangement), and in many cases, the removal of anti-oncogene function. In the most malignant and untreatable tumors, normal restraints on cell growth are completely lost as transformed cells escape from their primary sites and metastasize to other locations in the body. One reason for the enhanced growth and invasive properties of some tumors may be the acquisition of increasing numbers of mutations in oncogenes, with cumulative effect (Bear et al., Proc. Natl. Acad. Sci. USA 86:7495–7499, (1989)).
Alternatively, insofar as oncogenes function through the normal cellular signaling pathways required for organismal growth and cellular function (reviewed in McCormick, Nature 363:15–16, (1993)), additional alterations in the oncogenic signaling pathways may also contribute to tumor malignancy (Gilks et al., Mol. Cell Biol. 13:1759–1768, (1993)), even though mutations in the signaling pathways alone may not cause cancer.
Several discrete classes of proteins are known to be involved in bringing about the different types of changes in cell division properties and morphology associated with transformation. These changes can be summarized as, first, the promotion of continuous cell cycling (immortalization); second, the loss of responsiveness to growth inhibitory signals and cell apoptotic signals; and third, the morphological restructuring of cells to enhance invasive properties.
The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover approximately 50% to 60% of people contracting cancer will eventually succumb to the disease. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy.
Due to the wide variety of cancers presently observed, numerous anticancer agents have been developed to destroy cancer within the body. These compounds are administered to cancer patients with the objective of destroying or otherwise inhibiting the growth of malignant cells while leaving normal, healthy cells undisturbed. Anticancer agents have been classified based upon their mechanism of action. One type of chemotherapeutic is referred to as a metal coordination complex. It is believed this type of chemotherapeutic forms predominantly inter-strand DNA cross links in the nuclei of cells, thereby preventing cellular replication. As a result, tumor growth is initially repressed, and then reversed. Another type of chemotherapeutic is referred to as an alkylating agent. These compounds function by inserting foreign compositions or molecules into the DNA of dividing cancer cells. As a result of these foreign moieties, the normal functions of cancer cells are disrupted and proliferation is prevented. Another type of chemotherapeutic is an antineoplastic agent. This type of agent prevents, kills, or blocks the growth and spread of cancer cells. Still other types of anticancer agents include nonsteroidal aromastase inhibitors, bifunctional alkylating agents, etc.
Unfortunately, deleterious side effects are associated with each of these agents. For example, fluorouracil, a commonly used antineoplastic agent causes swelling or redness of normal skin, black or tarry stools, blood in the urine, chest pain, confusion, diarrhea, shortness of breath, and drowsiness. Administration of fluorouracil has also been associated with fever, chills, cough, sore throat, lower back pain, mouth sores, nausea, vomiting, pain and/or difficulty passing urine. Taxane administration has been associated with cardiovascular events such as syncope, rhythm abnormalities, hypertension and venous thrombosis; bone marrow suppression; neutropenia; anemia; peripheral neuropathy arthralgia/myalgia; nausea/vomiting and alopecia, to name only a few.
Combretastatins are another class of anticancer agents. Combretastatins have been isolated from stem wood of the African tree combretum caffrum (Combretaceae), and are potent inhibitors of microtubulin assembly. Combretastatin A-4 (CA-4) is significantly active against the US National Cancer Institute's (NCI) murine L1210 and P338 lymphocytic leukemia cell lines. In addition, CA-4 was found to compete with combretastatin A-1 (CA-1), another compound isolated from Combretum caffrum, as a potent inhibitor of colchicine binding to tubulin. CA-4 also strongly retards the growth of certain cell lines (ED50<0.01 (g/ml), and is a powerful anti-mitotic agent. See U.S. Pat. No. 4,996,237. Furthermore, an “anti-vascular” mechanism of action for both CA-4 and CA-1 has recently been discovered. Since the solubility of the combretastatins is very limited, prodrugs have been developed, such as combretastatin A-4 phosphate disodium salt and combretastatin A-1 phosphate disodium salt (hereinafter “CA4P” and “CA1P” respectively), to increase the solubility, and thus the efficacy of CA-4 and CA-1. In particular, a number of studies have shown that administration of combretastatin A-4 disodium salt or combretastatin A-1 phosphate disodium salt causes an extensive shut-down of blood flow to the tumor vasculature, leading to secondary tumor cell death. Toxic side effects of CA-4 have also been reported.
There is thus a need in the art to provide superior effective anticancer therapies which minimize patient exposure and the unwanted side effects associated with such agents.